Processes for producing racemic piperidine derivative and for producing optically active piperidine derivative

ABSTRACT

Disclosed are a method for producing racemic piperidine derivatives by processing optically-active piperidine derivatives in a hydrogen atmosphere in the presence of a reducing catalyst; and a method for producing optically-active piperidine derivatives or their acid salts by optically resolving the racemic piperidine derivatives obtained in the former method.

TECHNICAL FIELD

[0001] The present invention is to provide a method for producingracemic piperidine derivatives by racemizing unnecessary opticalantipodes, by-products of optical resolution to give optically-activepiperidine derivatives of general formulae (1), (2) and (3):

[0002] wherein R¹ represents a lower alkyl group having from 1 to 4carbon atoms, a phenyl group, or an aralkyl group; R², R³ and R⁴ may bethe same or different, each representing a hydrogen atom, an alkylgroup, a phenyl group, an aralkyl group, an alkoxycarbonyl group, analkylsulfonyl group, an arylsulfonyl group, an aralkylsulfonyl group, oran acyl group; R⁵ represents an alkyl group, a phenyl group, an aralkylgroup, an alkoxycarbonyl group, an alkylsulfonyl group, an arylsulfonylgroup, an aralkylsulfonyl group, or an acyl group.

[0003] The optically-active piperidine derivatives are useful formedicines and their intermediates. In particular, hydrochloride ofoptically-active 3-[3-(methylsulfonyl)phenyl]-1-propylpiperidinehydrochloride salt of formula (6) is a compound useful for medicines forParkinson's disease.

BACKGROUND ART

[0004] For obtaining optically-active piperidine derivatives, theirracemates may be subjected to optical resolution. However, itstheoretical yield is 50% of the racemates, and the process isunsatisfactory for industrial use. Therefore, if unnecessary opticalantipodes could be racemized and recycled for the starting materials foroptical resolution, the yield of the intended optically-activepiperidine derivatives would be approximately 100% in theory.Accordingly, racemization of optically-active piperidine derivatives togive racemic piperidine derivatives is an important technique. However,no one knows at all a method for racemizing optically-active piperidinederivatives of general formulae (1), (2) and (3):

[0005] wherein R¹ represents a lower alkyl group having from 1 to 4carbon atoms, a phenyl group, or an aralkyl group; R², R³ and R⁴ may bethe same or different, each representing a hydrogen atom, an alkylgroup, a phenyl group, an aralkyl group, an alkoxycarbonyl group, analkylsulfonyl group, an arylsulfonyl group, an aralkylsulfonyl group, oran acyl group; R⁵ represents an alkyl group, a phenyl group, an aralkylgroup, an alkoxycarbonyl group, an alkylsulfonyl group, an arylsulfonylgroup, an aralkylsulfonyl group, or an acyl group.

[0006] On the other hand, for producing optically-active3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine, for example, known area method of deriving it from optically-active3-(3-hydroxyphenyl)-1-propylpiperidine (J. Med. Chem., 1994, 37,2735-2753); and a method that comprises optically resolving racemic3-[3-(methylsulfonyl)phenyl]piperidine with optically-active tartaricacid followed by reacting the resulting product with propionaldehyde andreducing it (Tetrahedron Letters, Vol. 35, No. 48, 9063-9066).

[0007] However, the method of deriving the compound fromoptically-active 3-(3-hydroxyphenyl)-1-propylpiperidine often involvesracemization as it includes multiple steps in which the compounds beingprocessed are kept all the time optically active, and its yield to givethe intended optically-active3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine of high optical purityis low.

[0008] In the method that comprises optically resolving racemic3-[3-(methylsulfonyl)phenyl]piperidine with optically-active tartaricacid followed by deriving the intended compound from the resultingintermediate, the yield of optical resolution is low and, in addition,the optical purity of optically-active3-[3-(methylsulfonyl)phenyl]piperidine is low.

DISCLOSURE OF THE INVENTION

[0009] The present invention is to provide a method of racemizingoptically-active piperidine derivatives of optical antipodes,by-products in producing optically-active piperidine derivatives, and toprovide a method of optically resolving the racemic derivatives forobtaining the necessary optically-active piperidine derivatives or theiracid salts.

[0010] The constitution of the invention is as follows:

[0011] (1) A method for producing racemic piperidine derivatives, whichcomprises processing an optically-active piperidine derivative of any ofgeneral formulae (1), (2) and (3):

[0012]  wherein R¹ represents a lower alkyl group having from 1 to 4carbon atoms, a phenyl group, or an aralkyl group; R², R³ and R⁴ may bethe same or different, each representing a hydrogen atom, an alkylgroup, a phenyl group, an aralkyl group, an alkoxycarbonyl group, analkylsulfonyl group, an arylsulfonyl group, an aralkylsulfonyl group, oran acyl group; R⁵ represents an alkyl group, a phenyl group, an aralkylgroup, an alkoxycarbonyl group, an alkylsulfonyl group, an arylsulfonylgroup, an aralkylsulfonyl group, or an acyl group, in a hydrogenatmosphere in the presence of a reducing catalyst.

[0013] (2) The method for producing racemic piperidine derivatives ofabove (1), wherein the reducing catalyst contains a metal of Group VIIIof the Periodic Table.

[0014] (3) The method for producing racemic piperidine derivatives ofabove (2), wherein the metal of Group VIII of the Periodic Table isplatinum.

[0015] (4) The method for producing racemic piperidine derivatives ofany one of above (1) to (3), wherein the hydrogen atmosphere is apressure system of at least 0.2 MPa.

[0016] (5) The method for producing racemic piperidine derivatives ofany of above (1) to (4), wherein the optically-active piperidinederivative is one represented by a formula (4) or (5):

[0017]  wherein R¹ represents a lower alkyl group having from 1 to 4carbon atoms; and R⁴ represents an alkylsulfonyl group having from 1 to4 carbon atoms.

[0018] (6) The method for producing racemic piperidine derivatives ofany one of above (1) to (5), wherein the optically-active piperidinederivative is optically-active3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine of a formula (6):

[0019] (7) A method for producing optically-active piperidinederivatives or their acid salts, which comprises optically resolving theracemic piperidine derivative obtained in any one of above (1) to (6).

[0020] (8) The method for producing optically-active piperidinederivatives or their acid salts of above (7), wherein theoptically-resolving agent is an O,O′-diacyltartaric acid.

[0021] (9) The method for producing optically-active piperidinederivatives or their acid salts of above (7), wherein theoptically-active O,O′-diacyltartaric acid derivative is represented bythe following general formula (7):

[0022]  wherein R⁶ and R⁷ each represent a hydrogen atom, a halogenatom, an alkyl group having from 1 to 3 carbon atoms, an alkoxyl grouphaving from 1 to 3 carbon atoms, or a nitro group, and R⁶ and R⁷ may bethe same or different.

[0023] (10) The method for producing optically-active piperidinederivatives or their acid salts of above (9), wherein R⁶ and R⁷ informula (7) each are any of a hydrogen atom, a methyl group and amethoxy group.

[0024] (11) The method for producing optically-active piperidinederivatives or their acid salts of above (10), wherein R⁶ in formula (7)is a hydrogen atom, and R⁷ therein is any of a hydrogen atom, a methylgroup or a methoxy group.

[0025] (12) The method for producing optically-active piperidinederivatives or their acid salts of above (11), wherein theoptically-active O,O′-diacyltartaric acid is any of optically-activedibenzoyltartaric acid, optically-active di-p-toluoyltartaric acid oroptically-active dianisoyltartaric acid.

BEST MODE FOR CARRYING OUT THE INVENTION

[0026] The starting substances for use in the invention,optically-active piperidine derivatives are any of the following generalformulae (1), (2) and (3):

[0027] wherein R¹ represents a lower alkyl group having from 1 to 4carbon atoms, a phenyl group, or an aralkyl group; R², R³ and R⁴ may bethe same or different, each representing a hydrogen atom, an alkylgroup, a phenyl group, an aralkyl group, an alkoxycarbonyl group, analkylsulfonyl group, an arylsulfonyl group, an aralkylsulfonyl group, oran acyl group; R⁵ represents an alkyl group, a phenyl group, an aralkylgroup, an alkoxycarbonyl group, an alkylsulfonyl group, an arylsulfonylgroup, an aralkylsulfonyl group, or an acyl group. Of those, preferredfor racemization are optically-active piperidine derivatives of formula(1) or (2); and more preferred are optically-active piperidinederivatives of the following general formula (4) or (5):

[0028] wherein R¹ represents a lower alkyl group having from 1 to 4carbon atoms; and R⁴ represents an alkylsulfonyl group having from 1 to4 carbon atoms.

[0029] In particular, the invention is especially favorable forproducing racemic 3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine of aformula (6):

[0030] The optically-active piperidine derivative referred to herein ismeant to indicate a piperidine derivative of which the amount of oneoptical isomer is larger than that of the other optical isomer,substantially indicating such a piperidine derivative having an opticalpurity of at least 30% e.e.

[0031] The racemic piperidine derivative also referred to herein ismeant to indicate a piperidine derivative of which the optical purity islower than that of the starting compound for it, substantiallyindicating such a piperidine derivative having an optical purity oflower than 30% e.e.

[0032] The racemization in the invention may be effected in the absenceof a solvent, but is preferably effected in an inert organic solvent.Concretely, any of hydrocarbons such as benzene, toluene, xylene,hexane, octane, decane, cyclohexane; alcohols such as methanol, ethanol,propanol, isopropanol, butanol, isobutanol, t-butanol; ethers such asethyl ether, isopropylether, butylether, isobutyl ether,tetrahydrofuran, dioxane; or their mixed solvents may be used for thereaction solvent. These solvents may contain water. The amount of thesolvent for use herein is not specifically defined, but is preferably atmost 50 times by volume relative to the substrate from the economicalviewpoint.

[0033] The reducing catalyst for use in the invention is preferably acatalyst that contains a noble metal of Group VIII of the PeriodicTable, such as nickel, cobalt, ruthenium, rhodium, palladium orplatinum, more preferably a catalyst that contains platinum. Itsmorphology is not specifically defined. For example, herein usable areRaney catalysts such as Raney nickel, Raney cobalt; and catalysts ofruthenium, rhodium, palladium or platinum held on activated charcoal,alumina or asbestos. These catalysts may be used either singly or ascombined. The amount of the catalyst to be used is not specificallydefined, but preferably falls between 0.01 and 0.5 times by weightrelative to the optically-active piperidine derivative to be processedwith it.

[0034] The reaction is effected preferably at a temperature not lowerthan 100° C., more preferably not lower than 150° C.; and the hydrogenpressure for the reaction is preferably at least 0.2 MPa. The time forracemization depends on the reaction temperature, the hydrogen pressure,the type of the catalyst used and the amount of the catalyst used,generally falling between 5 and 40 hours.

[0035] The intended product, racemic piperidine derivative racemizedherein may be taken out by concentrating the filtrate of the reactionmixture from which the catalyst has been removed through filtrationafter the reaction.

[0036] Thus obtained herein, the racemic piperidine derivatives areusable as the starting materials for diastereomer salt resolution.

[0037] The optically-resolving agent for use in the invention isselected from optically-active O,O′-diacyltartaric acids, of which theD-forms and the L-forms may be selectively used herein in accordancewith the object of the invention.

[0038] For the optically-active O,O′-diacyltartaric acids, for example,compounds of the following general formula (7) are usable.

[0039] wherein R⁶ and R⁷ each represent a hydrogen atom, a halogen atom,an alkyl group having from 1 to 3 carbon atoms, an alkoxyl group havingfrom 1 to 3 carbon atoms, or a nitro group, and R⁶ and R⁷ may be thesame or different.

[0040] Of such O,O′-diacyltartaric acids of formula (7), preferred foruse herein are those in which R⁶ and R⁷ each are any of a hydrogen atom,a methyl group and a methoxy group, and more preferred are those inwhich R⁶ is a hydrogen atom and R⁷ is any of a hydrogen atom, a methylgroup or a methoxy group. Concretely, for example, they includeoptically-active dibenzoyltartaric acid, optically-activedi-p-toluoyltartaric acid, optically-active dianisoyltartaric acid andtheir hydrates.

[0041] These optically-active tartaric acid derivatives may be readilyproduced from optically-active tartaric acid in any known method.

[0042] The starting material in the invention, racemic piperidinederivative may be not only a 50/50 mixture of S-form and R-form isomersbut also any other mixtures in which the amount of any one of theoptical isomers is larger than that of the other one.

[0043] The starting racemic piperidine derivative is brought intocontact with from 0.4 to 1.5 mols, but preferably from 0.7 to 1.2 mols,relative to the starting racemic piperidine derivative, of such anoptically-active O,O′-diacyltartaric acid in a solvent to give adiastereomer salt. If desired, an organic carboxylic acid such as formicacid, acetic acid or propionic acid may be present in the reactionsystem. The amount of the organic carboxylic acid that may be in thesystem may fall between 0.8 and 1.5 mols, but preferably between 0.9 and1.2 mols, relative to one mol of the racemic piperidine derivative andin terms of the sum total of the acid and the optically-resolving agentused in the system.

[0044] The solvent to be in the system may be any and every one notchemically degrading both the piperidine derivative and theoptically-resolving agent in the solution containing them, but havingthe ability to precipitate any one diastereomer salt formed therein. Forit, for example, usable are any of water; alcohols such as methanol,ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, tert-butanol;ketones such as acetone, methyl ethyl ketone; other organic solventssuch as acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,3-dioxolane,chloroform, chlorobenzene; and their mixed solvents.

[0045] Regarding the mode of contacting the racemic piperidinederivative with the optically-resolving agent, both the racemicpiperidine derivative and the optically-resolving agent may be added tothe solvent all at a time, or they may be added thereto one afteranother. In case where an organic carboxylic acid is present in thereaction system, they may be added to the solvent all at a time, or maybe added thereto one after another. The order of adding them to thesolvent is not specifically defined.

[0046] The solution that contains the diastereomer salts thus formedtherein is cooled and/or concentrated, whereby one diastereomer salthardly soluble in the solution is precipitated therein.

[0047] The temperature at which the hardly-soluble diastereomer salt isprecipitated in the solution may fall between the freezing point and theboiling point of the solvent used, and may be suitably determined inaccordance with the object of the invention. Generally, the preferredrange of the temperature falls between −20° C. and 50° C.

[0048] The crystal of the hardly-soluble diastereomer salt may bereadily separated in any ordinary solid-liquid separation such asfiltration or centrifugation. Thus separated, the hardly-solublediastereomer salt crystal may be subjected to recrystallization orre-slurry washing to be the intended diastereomer salt of high purity.

[0049] Thus obtained, the diastereomer salt is desalted in any suitablemanner, whereby the intended optically-active piperidine derivative maybe separated from the optically-resolving agent and the two may beseparately collected.

[0050] Desalting the diastereomer salt may be effected in any knownmanner, for which, for example, employable is a method of processing thesalt with an acid or alkali in an aqueous solvent or a method ofprocessing it with an ion-exchange resin. Concretely, the diastereomersalt is desalted in an aqueous solution of an alkali such as sodiumhydroxide in water, and then extracted with an organic solvent such asisopropyl ether. Through the process, the desalted piperidine derivativeis extracted out in the organic phase, and the resulting extract isconcentrated to obtain the intended, optically-active piperidinederivative. Next, a mineral acid such as hydrochloric acid or sulfuricacid is added to the aqueous phase from which the piperidine derivativehas been removed so that the aqueous phase may have a pH of from 1 to 2,and the optically-resolving agent thus precipitated in the resultingaqueous phase is taken out through filtration. Alternatively, theoptically-resolving agent in the aqueous phase is extracted with anorganic solvent such as dichloromethane. In that manner, theoptically-resolving agent is collected.

[0051] Thus obtained, the optically-active piperidine derivative isreacted with a mineral acid such as hydrochloric acid or sulfuric acidor with an organic acid such as formic acid, acetic acid or propionicacid to give an acid salt of the piperidine derivative.

[0052] The optically-active3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine is useful for medicines.

EXAMPLES

[0053] The invention is described in more detail with reference to thefollowing Examples, which, however, are not intended to restrict thescope of the invention.

[0054] The optical purity of3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine obtained in the Exampleswas obtained according to the following method: From 8 to 10 mg of3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine is dissolved in 10 ml ofan n-hexane solution that contains 25% ethanol, and 20 μl of theresulting solution is analyzed through HPLC. The column used for theanalysis is Chiralpak AS (Daicel); and the mobile phase isisohexane/methanol/diethylamine=97.5/2.5/0.1 (v/v/v). The columntemperature is about 25° C.: the flow rate is 0.60 ml/min; and UV (267nm) is used for detection.(R)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine is detected in 24.5minutes, and (S)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine isdetected in 26.1 minutes.

Example 1

[0055] 0.49 g of (R)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine(optical purity, 61% e.e.), 0.20 g of 5% platinum/activated charcoal(wet) and 5 ml of ethanol were put in to a 100-ml autoclave, andprocessed therein under a hydrogen pressure of 0.5 MPa and at atemperature of 180° C. for 21 hours. After the reaction, the autoclavewas cooled and opened, and the reaction mixture therein was filtered toremove the catalyst. The resulting filtrate was concentrated to obtain0.52 g of pale yellow oil. Its optical purity was 0% e.e., and thedegree of racemization in this process was 100%.

Example 2

[0056] 0.53 g of (R)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine(optical purity, 61% e.e.), 0.20 g of 5% platinum/activated charcoal(wet) and 5 ml of ethanol were put in to a 100-ml autoclave, andprocessed therein under a hydrogen pressure of 1.0 MPa and at atemperature of 180° C. for 21 hours. After the reaction, the autoclavewas cooled and opened, and the reaction mixture therein was filtered toremove the catalyst. The resulting filtrate was concentrated to obtain0.53 g of pale yellow oil. Its optical purity was 0% e.e., and thedegree of racemization in this process was 100%.

Example 3

[0057] 0.50 g of (R)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine(optical purity, 61% e.e.), 0.20 g of 5% platinum/activated charcoal(wet) and 5 ml of n-propanol were put into a 100-ml autoclave, andprocessed therein under a hydrogen pressure of 1.0 MPa and at atemperature of 180° C. for 18 hours. After the reaction, the autoclavewas cooled and opened, and the reaction mixture therein was filtered toremove the catalyst. The resulting filtrate was concentrated to obtain0.50 g of pale yellow oil. Its optical purity was 0% e.e., and thedegree of racemization in this process was 100%.

Example 4

[0058] 35 g of (R)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine(optical purity, 61% e.e.), 14 g of 5% platinum/activated charcoal (wet)and 350 ml of n-propanol were put into a 500-ml autoclave, and processedtherein under a hydrogen pressure of 1.0 MPa and at a temperature of180° C. for 19 hours. After the reaction, the autoclave was cooled andopened, and the reaction mixture therein was filtered to remove thecatalyst. The resulting filtrate was concentrated to obtain 36.5 g ofpale yellow oil. Its optical purity was 0% e.e., and the degree ofracemization in this process was 100%.

Example 5

[0059] 0.49 g of (R)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine(optical purity, 61% e.e.), 0.20 g of 5% platinum/activated charcoal(wet) and 5 ml of n-butanol were put into a 100-ml autoclave, andprocessed therein under a hydrogen pressure of 1.0 MPa and at atemperature of 180° C. for 21 hours. After the reaction, the autoclavewas cooled and opened, and the reaction mixture therein was filtered toremove the catalyst. The resulting filtrate was concentrated to obtain0.52 g of pale yellow oil. Its optical purity was 0% e.e., and thedegree of racemization in this process was 100%.

Example 6

[0060] 0.53 g of (R)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine(optical purity, 61% e.e.), 0.20 g of 5% ruthenium/activated charcoal(wet) and 5 ml of ethanol were put into a 100-ml autoclave, andprocessed therein under a hydrogen pressure of 1.0 MPa and at atemperature of 180° C. for 21 hours. After the reaction, the autoclavewas cooled and opened, and the reaction mixture therein was filtered toremove the catalyst. The resulting filtrate was concentrated to obtain0.57 g of pale yellow oil. Its optical purity was 43% e.e., and thedegree of racemization in this process was 30%.

Example 7

[0061] 0.52 g of (R)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine(optical purity, 61% e.e.), 0.20 g of 5% rhodium/activated charcoal(wet) and 5 ml of ethanol were put into a 100-ml autoclave, andprocessed therein under a hydrogen pressure of 1.0 MPa and at atemperature of 180° C. for 21 hours. After the reaction, the autoclavewas cooled and opened, and the reaction mixture therein was filtered toremove the catalyst. The resulting filtrate was concentrated to obtain0.55 g of pale yellow oil. Its optical purity was 46% e.e., and thedegree of racemization in this process was 25%.

Example 8

[0062] 0.53 g of (R)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine(optical purity, 61% e.e.), 0.20 g of Raney nickel (wet) and 5 ml ofethanol were put into a 100-ml autoclave, and processed therein under ahydrogen pressure of 1.0 MPa and at a temperature of 180° C. for 21hours. After the reaction, the autoclave was cooled and opened, and thereaction mixture therein was filtered to remove the catalyst. Theresulting filtrate was concentrated to obtain 0.56 g of pale yellow oil.Its optical purity was 58% e.e., and the degree of racemization in thisprocess was 5%.

Example 9

[0063] 0.51 g of (R)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine(optical purity, 61% e.e.), 0.20 g of 5% platinum/activated charcoal(wet) and 5 ml of toluene were put into a 100-ml autoclave, andprocessed therein under a hydrogen pressure of 1.0 MPa and at atemperature of 150° C. for 20 hours. After the reaction, the autoclavewas cooled and opened, and the reaction mixture therein was filtered toremove the catalyst. The resulting filtrate was concentrated to obtain0.53 g of pale yellow oil. Its optical purity was 57% e.e., and thedegree of racemization in this process was 7%.

Example 10

[0064] 0.51 g of (R)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine(optical purity, 61% e.e.), 0.20 g of 5% platinum/activated charcoal(wet) and 5 ml of isopropyl ether were put into a 100-ml autoclave, andprocessed therein under a hydrogen pressure of 1.0 MPa and at atemperature of 150° C. for 20 hours. After the reaction, the autoclavewas cooled and opened, and the reaction mixture therein was filtered toremove the catalyst. The resulting filtrate was concentrated to obtain0.54 g of pale yellow oil. Its optical purity was 55% e.e., and thedegree of racemization in this process was 10%.

Example 11

[0065] 3.7 g of (R)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine(optical purity, 50% e.e.), 1.6 g of 5% platinum/activated charcoal(wet) and 40 ml of ethanol were put into a 100-ml autoclave, andprocessed therein under a hydrogen pressure of 1.0 MPa and at atemperature of 180° C. for 18 hours. After the reaction, the autoclavewas cooled and opened, and the reaction mixture therein was filtered toremove the catalyst. The resulting filtrate was concentrated to obtain4.0 g of pale yellow oil. Its optical purity was 0% e.e., and the degreeof racemization in this process was 100%.

Example 12

[0066] 11.00 g of the racemic3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine obtained in the processof Example 4 (purity, 94.0%; 36.7 mmols), 16.18 g (40.0 mmols) ofdi-p-toluoyl-D-tartaric acid monohydrate and 150 ml of acetonitrile wereput into a 200-ml flask, and heated at 40° C. to form a uniformsolution. The solution was cooled to 20° C., and 50 mg of(R)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidinedi-p-toluoyl-D-tartrate was added thereto and then stirred at 18 to 22°C. for 7 hours. The resulting precipitate was taken out throughfiltration and then dried to obtain 7.70 g of(R)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidinedi-p-toluoyl-D-tartrate. In the crystal, the content of3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine was 41.3%, and theoptical purity thereof was 90.6% e.e.

Example 13

[0067] 11.05 g of the racemic3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine obtained in the processof Example 4 (purity, 94.0%; 36.9 mmols), 16.18 g (40.0 mmols) ofdi-p-toluoyl-L-tartaric acid monohydrate and 150 ml of acetonitrile wereput into a 200-ml flask, and heated at 40° C. to form a uniformsolution. The solution was cooled to 20° C., and 50 mg of(S)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidinedi-p-toluoyl-L-tartrate was added thereto and then stirred at 18 to 20°C. for 9 hours. The resulting precipitate was taken out throughfiltration and then dried to obtain 10.05 g of(S)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidinedi-p-toluoyl-L-tartrate. In the crystal, the content of3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine was 41.8%, and theoptical purity thereof was 90.8% e.e.

Example 14

[0068] 11.02 g of the racemic3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine obtained in the processof Example 4 (purity, 92.8%; 36.3 mmols), 15.06 g (40.4 mmols) ofdibenzoyl-D-tartaric acid monohydrate and 85 ml of acetonitrile were putinto a 100-ml flask, and stirred at about 30° C. to form a uniformsolution. The solution was cooled to 3° C., and 50 mg of(S)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine dibenzoyl-D-tartratewas added thereto and then stirred at 0 to 3° C. for 23 hours. Theresulting precipitate was taken out through filtration and then dried toobtain 8.67 g of (S)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidinedibenzoyl-D-tartrate. In the crystal, the content of3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine was 41.3%, and theoptical purity thereof was 88.0% e.e.

Example 15

[0069] 11.08 g of the racemic3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine obtained in the processof Example 4 (purity, 92.8%; 36.5 mmols), 16.73 g (40.0 mmols) ofdianisoyl-D-tartaric acid and 200 ml of acetonitrile were put into a300-ml flask, and heated at 50° C. to form a uniform solution. Thesolution was cooled to 30° C., and stirred at 27 to 30° C. for 3 hours.The resulting precipitate was taken out through filtration and thendried to obtain 11.99 g of(S)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidinedianisoyl-D-tartrate. In the crystal, the content of3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine was 38.8%, and theoptical purity thereof was 92.3% e.e.

INDUSTRIAL APPLICABILITY

[0070] According to the present invention, racemic piperidinederivatives are efficiently obtained in an industrial process. Using theoptically-resolving agent of the invention enables a high yield ofoptically-active piperidine derivatives or their acid salts of highoptical purity. These are usable for medicines or their intermediates.

1. A method for producing racemic piperidine derivatives, whichcomprises processing an optically-active piperidine derivative of any ofgeneral formulae (1), (2) and (3):

wherein R¹ represents a lower alkyl group having from 1 to 4 carbonatoms, a phenyl group, or an aralkyl group; R², R³ and R⁴ may be thesame or different, each representing a hydrogen atom, an alkyl group, aphenyl group, an aralkyl group, an alkoxycarbonyl group, analkylsulfonyl group, an arylsulfonyl group, an aralkylsulfonyl group, oran acyl group; R⁵ represents an alkyl group, a phenyl group, an aralkylgroup, an alkoxycarbonyl group, an alkylsulfonyl group, an arylsulfonylgroup, an aralkylsulfonyl group, or an acyl group, in a hydrogenatmosphere in the presence of a reducing catalyst.
 2. The method forproducing racemic piperidine derivatives as claimed in claim 1, whereinthe reducing catalyst contains a metal of Group VIII of the PeriodicTable.
 3. The method for producing racemic piperidine derivatives asclaimed in claim 2, wherein the metal of Group VIII of the PeriodicTable is platinum.
 4. The method for producing racemic piperidinederivatives as claimed in any one of claims 1 to 3, wherein the hydrogenatmosphere is a pressure system of at least 0.2 MPa.
 5. The method forproducing racemic piperidine derivatives as claimed in any of claims 1to 4, wherein the optically-active piperidine derivative is onerepresented by a formula (4) or (5):

wherein R¹ represents a lower alkyl group having from 1 to 4 carbonatoms; and R⁴ represents an alkylsulfonyl group having from 1 to 4carbon atoms.
 6. The method for producing racemic piperidine derivativesas claimed in any one of claims 1 to 5, wherein the optically-activepiperidine derivative is optically-active3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine of a formula (6):


7. A method for producing optically-active piperidine derivatives ortheir acid salts, which comprises optically resolving the racemicpiperidine derivative obtained in any one of claims 1 to
 6. 8. Themethod for producing optically-active piperidine derivatives or theiracid salts as claimed in claim 7, wherein the optically-resolving agentis an O,O′-diacyltartaric acid.
 9. The method for producingoptically-active piperidine derivatives or their acid salts as claimedin claim 7, wherein the optically-active O,O′-diacyltartaric acidderivative is represented by the following general formula (7):

wherein R⁶ and R⁷ each represent a hydrogen atom, a halogen atom, analkyl group having from 1 to 3 carbon atoms, an alkoxyl group havingfrom 1 to 3 carbon atoms, or a nitro group, and R⁶ and R⁷ may be thesame or different.
 10. The method for producing optically-activepiperidine derivatives or their acid salts as claimed in claim 9,wherein R⁶ and R⁷ in formula (7) each are any of a hydrogen atom, amethyl group and a methoxy group.
 11. The method for producingoptically-active piperidine derivatives or their acid salts as claimedin claim 10, wherein R⁶ in formula (7) is a hydrogen atom, and R⁷therein is any of a hydrogen atom, a methyl group or a methoxy group.12. The method for producing optically-active piperidine derivatives ortheir acid salts as claimed in claim 11, wherein the optically-activeO,O′-diacyltartaric acid is any of optically-active dibenzoyltartaricacid, optically-active di-p-toluoyltartaric acid or optically-activedianisoyltartaric acid.